Deconvolution and interruption of the cancer-neuro-immune axis facilitating brain metastases

癌症-神经-免疫轴的解卷积和中断促进脑转移

• 批准号: 10706491
• 负责人: Melanie Hayden Gephart
• 金额: $ 147.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706491
• 关键词: Address; Advocate; Biology; Brain; Brain Neoplasms; CRISPR library; Cancer Patient; Clinical; Clinical Trials; Communication; Communities; Data; Dedications; Deterioration; Development; Diagnostic; Disease model; Ensure; Exclusion; Experimental Models; Foundations; Goals; Human; Immune system; Immunotherapy; In Vitro; Incidence; Interruption; Malignant Neoplasms; Mediator; Metastatic malignant neoplasm to brain; Methods; Microglia; Modeling; Molecular; Mus; Neoplasm Metastasis; Neuroimmune; Neurologic; Office of Administrative Management; Organoids; Patient risk; Patients; Physicians; Primary Neoplasm; Production; Productivity; Quality of life; Research; Sampling; Scientist; Site; Specimen; Technology; Testing; Therapeutic; Translating; Translations; Tropism; Tumor Tissue; Work; brain cell; data management; design; experience; glycoproteomics; high throughput screening; human disease; human tissue; improved; in vivo Model; innovation; insight; interest; multidisciplinary; neoplastic cell; neuropathology; new therapeutic target; novel; organizational structure; programs; synergism; therapy resistant; tool; tumor; tumor microenvironment

1 ABSTRACT – OVERALL COMPONENT 2 3 The development of brain metastases, experienced by up to 40% of cancer patients, marks a clear inflection 4 point in survival and quality of life. The inaccessibility of brain tumor tissue has stymied progress in our 5 understanding and treatment of brain metastases, and patients are regularly excluded from clinical trials. The 6 Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improving our 7 understanding and treatment of brain metastases, a currently increasing yet underserved subset of cancer 8 patients. To accomplish the above goal, we have: (1) designed an organizational structure that supports 9 scientists in our integrated work; (2) developed highly innovative and complementary Projects to understand 10 and disrupt the cancer-neuro-immune axis supporting brain metastases; and (3) created NeuroPathology 11 and ToolKit Cores to make human specimens and cutting-edge technologies readily accessible to participating 12 scientists. We expect to identify and target key mediators of brain metastasis, with therapeutic benefit for 13 patients. 14 Little is known about the distinct mechanisms that drive tumor cells to the brain and allow them to grow in this 15 unique microenvironment, supported in part by normal brain cells. Streamlined access to human brain 16 specimens, combined with innovations in modeling and manipulation of the tumor microenvironment, create this 17 collaborative opportunity for fundamental advancement. Our expert, integrated team of productive collaborators 18 aims to understand how the intrinsic features of tumor cells (Project 1), resident microglia (Project 2), and the 19 systemic immune system (Project 3) contribute to the onset and progression of brain metastases. These projects 20 are facilitated by centralized access to human patient brain metastases samples (NeuroPathology Core), and 21 novel, multiplexed analyses and disease modeling (ToolKit Core). Our multidisciplinary physician Consultant 22 Network provides clinical insight and helps in the rapid translation of our findings into clinical trials for patients 23 with brain metastases. The Administrative and Data Management Core will provide the operational support 24 necessary to successfully achieve the goals of the program. Our Patient Advocates help to integrate and 25 communicate our work to the greater scientific and patient communities. 26 We have formed one of the few groups with the expertise, interest, and capacity to address the underlying 27 mechanisms of and therapeutic opportunities for brain metastases. Only through this combined synergy would 28 this project be possible. These innovative methods will ensure our findings are reflective of and translatable to 29 the human disease, enabling our multidisciplinary team to lay the foundation for diagnostic and therapeutic 30 advancements.

1个抽象-整体组件 2. 高达40%的癌症患者都经历过脑转移，这标志着一个明显的转折点。 生存和生活质量4分。无法接触到脑肿瘤组织阻碍了我们的进展 5了解和治疗脑转移瘤，患者经常被排除在临床试验之外。这个 6斯坦福脑转移联盟统一了大脑和癌症专家的单一目标，即改善我们的 7了解和治疗脑转移癌，这是一种目前正在增加但未得到充分治疗的癌症亚类 8例。为实现上述目标，我们有：(1)设计了一个支持 9名科学家参与我们的综合工作；(2)开发了高度创新和互补性的项目，以了解 扰乱支持脑转移的癌症-神经免疫轴；以及(3)造成神经病理 11和工具包核心，使参与者可以随时获取人体标本和尖端技术 12名科学家。我们希望确定和定位脑转移的关键介质，并对其进行治疗 13例患者。 14关于驱动肿瘤细胞进入大脑并使它们在大脑中生长的不同机制，人们知之甚少 15独特的微环境，部分由正常脑细胞支持。简化了对人脑的访问 16个样本，结合肿瘤微环境建模和操作方面的创新，创造了这一点 17合作机会，实现根本进步。我们由富有成效的合作者组成的专家、综合团队 18旨在了解肿瘤细胞(项目1)、常驻小胶质细胞(项目2)和 19系统免疫系统(项目3)在脑转移瘤的发生和发展中起作用。这些项目 20个通过集中访问人类患者脑转移样本(神经病理学核心)而促进的，以及 21新的、多路分析和疾病建模(工具包核心)。我们的多学科医生顾问 22网络提供临床洞察并帮助将我们的发现快速转化为患者的临床试验 23例为脑转移瘤。行政和数据管理核心将提供业务支持 24成功实现该计划的目标所必需的。我们的患者权益倡导者帮助整合和 25将我们的工作传达给更大的科学和患者社区。 26我们已经成立了少数几个具有专业知识、兴趣和能力的小组之一，以解决潜在的 27脑转移瘤的机制和治疗机会。只有通过这种综合的协同效应才能 这个项目是可能的。这些创新的方法将确保我们的发现能够反映并可翻译成 29人类疾病，使我们的多学科团队能够为诊断和治疗奠定基础 30个进步。